Fibromyalgia is known as a diffuse periarticular musculoskeletal pain syndrome, primarily affecting femalse (90%) and is associated with insomnia, cognitive impairment, fatigue and depression. Fibromyalgia is also known to be associated with elevated levels of substance P (SP) in the cerebrospinal fluid (CSF), decreased levels of serotonin (5-HT) and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis. The pathophysiological mechanisms underlying fibromyalgia are unknown, and the condition is considered uncurable. Exercise, cognitive behavioral therapy and antidepressant medication have been shown to diminish the severity of symptoms in some patients, but most patients remain in an unremitting state of illness. Standard laboratory tests are normal for most patients having fibromyalgia, and there is no evidence for autoimmune disease. Interestingly, there is an association of fibromyalgia with a significantly higher incidence of childhood and adult physical and emotional abuse and/or trauma. However, these findings have not been reconciled until the discovery of this invention.
The hormone triiodithyronine (T3) is a product of the thyroid gland. T3 is synthesized in the thyroid gland and is released as thyroxine (T4). T4 is released from the thyroid gland in response to, among other things, a pituitary hormone, thyroid hormone releasing factor.
The hormone L-3,3′,5,5′,-tetraiodothyronine (L-thyronine or T4) is a product of the thyroid gland. T4 is an inactive hormone when it is released into the blood stream by the thyroid gland. As T4 circulates throughout the body, it is absorbed by cells. OnceT4 is within a cell it is converted by one of three enzymes (deiodinases) into either the active hormone L-3,3′5, -triiodothyronine (T3), the inactive T3 competitive product L-3,3′,5′-triiodothyronine referred to as reverse T3 (rT3) or the deactivated L-3,3′-diiodothyronine (T2). Type I deiodinase (D1) is responsible for plasma production of T3 and rT3 by deiodination of the outer ring 5′ position iodine to form T3 or deiodination of the inner ring 5 position iodine to form rT3. Type II deiodinase (D2) is responsible for intracellular deiodination and it's activity is limited to outer ring 5′ position deiodination to form T3 from T4. Type III deiodinase (D3) activity is limited to inner ring deiodination of T3 to the inactive T2 product. Types I and III deiodinases play a role in the inactivation of thyroid hormones through inner ring (5) deiodination of T4 to rT3 and T3 to T2. Type I and II 5′ deiodinase affects the outer ring and transforms rT3 to T2 or T4 to T3. The majority of T3 is produced in the liver and kidney and released into the blood stream, although most cells have the capacity to convert T4 to T3 or rT3.
T3 is metabolically active and stimulates production of cellular energy, and generally is an activator of tissues and organs. T3 acts by diffusing into cells, where it interacts with a cellular protein which transports the T3 to the cellular nucleus. T3 then acts by stimulating gene transcription to produce messenger ribonucleic acids (mRNA) of certain genes. Translation of the T3-induced mRNA produces cellular proteins that promote cellular activation. In contrast, rT3 has opposing effects, at least partially by inhibiting the action of T3, by way of competitively inhibiting T3 nuclear receptors in cells.
Thus, the balance between the effects of T3 and rT3 can determine the state of cellular activation. In Euthyroid Sick Syndrome (ESS), conversion of T4 to T3 is inhibited and conversion of T4 to rT3 is elevated. According to the American Thyroid Association, this condition does not warrant treatment. The American Psychiatric Association recognizes the use of T3 for treatment of depression, and levels of T3 are often decreased in patients with depression, as well as patients with fibromyalgia. Patients with fibromyalgia can have elevated levels of rT3. Dormant animals have elevated rT3 levels.
The so-called “Wilson's Syndrome” is reported to be diagnosed in patients having rT3 and T3 levels, reduced body temperature, and clinical findings of arthritis, muscular and joint aches, elevated cholesterol and several other findings.
Dementias are important causes of morbidity in people suffering from one or more of a variety of underlying disorders. Typically, dementias present as decreased mental clarity, decreased memory and complaints of low energy levels, resulting in reduced physical activity. In some patients, dementias also present with depression.
Treatment of dementias has been limited by the lack of understanding of underlying physiological and pathophysiological mechanisms leading to decreased mental functioning. Treatment of dementias typically are relatively ineffective, and many patients suffering from dementia, especially the elderly, do not improve. This is especially true of patients suffering from Alzheimer's disease, which is progressive and ultimately can be fatal. Because of the paucity of effective therapies, intense efforts are taking place to understand the underlying causes of dementias, including that associated with Alzheimer's disease, and to provide effective treatments for such conditions.
Latasa et al. reported that the β-amyloid protein, a major constituent of plaques observed in patients with advanced Alzheimer's disease, is at least partially under transcriptional control by thyroid hormones, including triiodythyronine (T3). Latasa noted three isoforms of alternatively spliced β-amyloid precursor protein (APP) mRNAs.
Belandia et al. (J. Biol. Chem. 273:30366-30371 (1998) reported that T3 can negatively regulate the expression of the APP gene in neuroblastoma cells. The hormone triiodithyronine (T3) is a product of the thyroid gland. T3 is synthesized in the thyroid gland and is released as thyroxine (T4). T4 is released from the thyroid gland in response to, among other things, a pituitary hormone, thyroid hormone releasing factor.
The hormone L-3,3′,5,5′,-tetraiodothyronine (L-thyronine or T4) is a product of the thyroid gland. T4 is an inactive hormone when it is released into the blood stream by the thyroid gland. As T4 circulates throughout the body, it is absorbed by cells. OnceT4 is within a cell it is converted by one of three enzymes (deiodinases) into either the active hormone L-3,3′5, -triiodothyronine (T3), the inactive T3 competitive product L-3,3′,5′-triiodothyronine referred to as reverse T3 (rT3) or the deactivated L-3,3′-diiodothyronine (T2). Type I deiodinase (D1) is responsible for plasma production of T3 and rT3 by deiodination of the outer ring 5′ position iodine to form T3 or deiodination of the inner ring 5 position iodine to form rT3. Type II deiodinase (D2) is responsible for intracellular deiodination and it's activity is limited to outer ring 5′ position deiodination to form T3 from T4. Type III deiodinase (D3) activity is limited to inner ring deiodination of T3 to the inactive T2 product. Types I and III deiodinases play a role in the inactivation of thyroid hormones through inner ring (5) deiodination of T4 to rT3 and T3 to T2. Types I and II 5′ deiodinase affects the outer ring and transforms rT3 to T2 or T4 to T3. The majority of T3 is produced in the liver and kidney and released into the blood stream, although most cells have the capacity to convert T4 to T3 or rT3.
T3 is metabolically active and stimulates production of cellular energy, and generally is an activator of tissues and organs. T3 acts by diffusing into cells, where it interacts with a cellular protein which transports the T3 to the cellular nucleus. T3 then acts by stimulating gene transcription to produce messenger ribonucleic acids (mRNA) of certain genes. Translation of the T3-induced mRNA produces cellular proteins that promote cellular activation. In contrast, rT3 has opposing effects, at least partially by inhibiting the action of T3, by way of competitively inhibiting T3 nuclear receptors in cells.
However, there was no known link between clinical dementia and thyroid hormones, and the effects of thyroid hormones on dementias in patients remained unknown until the discoveries that underly this invention.